CLINICAL REVIEW
Clinicopathologic features of chronic nonspecific multiple ulcersof the small intestine
Motohiro Esaki1 • Junji Umeno1• Takanari Kitazono1
• Takayuki Matsumoto2
Received: 27 February 2015 / Accepted: 6 March 2015 / Published online: 19 March 2015
� Springer Japan 2015
Abstract Chronic nonspecific multiple ulcers of the small
intestine is a rare but distinct clinical condition, character-
ized by multiple small intestinal ulcers of nonspecific his-
tology and chronic, persistent gastrointestinal bleeding
without nonsteroidal anti-inflammatory drug use. However,
because of the term ‘‘nonspecific’’ in its nomenclature, some
gastroenterologists have misinterpreted the disease as the
condition with small intestinal ulcers caused by undeter-
mined etiologies without considering clinical features. Such
misinterpretation has led to the heterogeneity of clinico-
pathologic features of the disease, as well as to ambiguity
regarding a possible genetic contribution. It thus seems
necessary to recognize the clinical entity of the disease
precisely to avoid misinterpretation. In this review, we de-
scribe the clinicopathologic features, differential diagnosis,
and the possibility of a genetic contribution to the disease.
Keywords Chronic nonspecific ulcer � Small intestine
Introduction
The clinical application of capsule endoscopy (CE) and bal-
loon-assisted enteroscopy (BAE) has led to the possibility of
encountering various small intestinal pathologies [1–3].
Among conditions manifesting small intestinal ulcers, Crohn’s
disease, intestinal tuberculosis, Behcet’s disease, and non-
steroidal anti-inflammatory drugs (NSAIDs) enteropathy are
conditions predisposing to chronic or recurrent small intestinal
ulcers, while there still remain cases with unknown etiologies.
We have previously reported on an unusual form of
enteropathy of unknown etiology, referred to as chronic
nonspecific multiple ulcers of the small intestine (CNSU),
which is characterized by chronic blood and protein loss
through persistent small intestinal ulcers [4–6]. Although
this rare but distinct clinicopathologic condition was ini-
tially reported in the Japanese literature by Okabe and
Sakimura [7], the term ‘‘nonspecific’’ in its nomenclature
which refers to the nonspecific histology of the ulcers has
occasionally led to the misinterpretation of the disease as
any condition with small intestinal ulcers of undetermined
etiology. In Western countries, although the clinicopatho-
logic features seem to be different from those of CNSU,
Perlemuter et al. [8] have reported a similar enteropathy,
termed ‘‘cryptogenic multifocal ulcerous stenosing enteritis
(CMUSE)’’. In addition, a recent review considered CNSU
to be identical to CMUSE [9]. Thus, precise recognition of
the clinical entity of CNSU is mandatory to avoid misin-
terpretation. In this review, we describe the clinicopatho-
logic features, differential diagnosis, and the possibility of
a genetic contribution to the disease.
Clinicopathologic features
Demographics, clinical symptoms, and laboratory
data
Table 1 summarizes the clinical features of 16 cases who
were diagnosed as having CNSU. The disease predominantly
& Motohiro Esaki
1 Department of Medicine and Clinical Science, Graduate
School of Medical Sciences, Kyushu University, Maidashi
3-1-1, Higashi-ku, Fukuoka 812-8582, Japan
2 Division of Gastroenterology, Department of Internal
Medicine, School of Medicine, Iwate Medical University,
Morioka, Japan
123
Clin J Gastroenterol (2015) 8:57–62
DOI 10.1007/s12328-015-0559-x
occurs in females, and the age at disease onset ranged from 7
to 53 years. Clinical symptoms of CNSU are mainly at-
tributable to chronic and persistent blood loss from small
intestinal ulcers. Patients usually manifest fatigue, edema, or
abdominal pain, while they rarely complain of diarrhea,
hematochezia, or fever. Although most patients have a his-
tory of long-term anemia, patients do not visit a gastroen-
terologist until long after disease onset because of their
uncertain abdominal symptoms, resulting in a delay in the
diagnosis of CNSU [6, 7, 10].
Laboratory data also reflect persistent blood loss from
the ulcers. Fecal occult blood tests are continuously posi-
tive and peripheral blood tests show hypochromatic and
microcytic anemia. Most patients also manifest hypopro-
teinemia and hypoalbuminemia. However, acute inflam-
matory reactions, including C-reactive protein, a1- and a2-
globulins, are usually within normal ranges or slightly in-
creased [6, 7]. Leukocyte and platelet counts also are
within normal ranges.
Small intestinal findings
The small intestinal ulcers in CNSU occur predominantly
in the ileum, while the terminal ileum is usually intact [7,
10]. The ulcers are multiple (usually [20) and each lesion
manifests a shallow and flat ulcer bed surrounded by a
discrete margin.
The configuration of each ulcer is usually linear or a tall
triangle, and the ulcer is aligned circularly or obliquely.
The ulcers occasionally fuse, thus showing a geographic
configuration. Such small intestinal lesions are radio-
graphically depicted as multiple rigidity or eccentric de-
formities (Fig. 1a, b). Sharply demarcated barium flecks
can also be depicted using compression study or double-
contrast barium study, although BAE is more suitable for
evaluation of the shallow ulcers of CNSU (Fig. 2a, b). In
Table 1 Summary of clinical characteristics of 16 patients with
CNSU
1. Gender
Female:male 13:3
2. Age at onseta 24.0 [7–53]
3. Age at diagnosisa 41.2 [7–66]
4. Symptoms
Anemia 16 (100 %)
Abdominal pain 6 (38 %)
Hypoproteinemia 3 (19 %)
Edema 1 (6 %)
5. Laboratory dataa
Hemoglobin (g/dl) 9.1 [4.8–11.2]
Serum protein (g/dl) 5.6 [3.8–8.2]
CRP (mg/dl) 0.4 [0–1.6]
6. Involved site
Stomach 5 (31 %)
Duodenum 8 (50 %)
Jejunum 3 (19 %)
Ileum 16 (100 %)
7. History of surgery
Present 13 (81 %)
Absent 3 (19 %)
a Data are expressed as mean [range]
Fig. 1 Small intestinal radiographic findings. a Double contrast radiography depicts intestinal stricture (arrow) and eccentric deformities.
b Sharply demarcated barium flecks (arrows) are depicted using compression study
58 Clin J Gastroenterol (2015) 8:57–62
123
addition to the particular configuration and alignment of
the ulcers, the ulcer bed is fragile and contact bleeding can
occasionally be seen under enteroscopy (Fig. 2c). In con-
trast, the intervening mucosa is apparently normal without
any diminutive lesions (Fig. 2d).
During the clinical course, the ulcers develop into in-
testinal strictures, mimicking the diaphragm-like strictures
seen in NSAID enteropathy (Fig. 3a). However, because of
the oblique nature of the pre-existing ulcers, the strictures
are not always concentric but may show spiral patterns
(Fig. 3b). CE should not be used due to the possible re-
tention or impaction of the capsule. Small intestinal lesions
of CNSU never progress to cobblestone appearance, fis-
sure, or fistula formation or adhesion.
Although CNSU mainly involves the ileum, there have
been cases of duodenal and colonic involvement [11, 12].
Gastroduodenal involvement was found in 11 of our 16
cases; however, the clinical significance of these lesions
needs to be clarified along with the status of Helicobacter
pylori infection.
Histologic findings
The main histologic characteristics of CNSU are the depth
and the healing process of small intestinal ulcers. The ulcer
depth is restricted to the mucosa or the submucosa, and it
never reaches the muscular layer [6, 7, 10]. The ulcer is
clearly demarcated by surrounding villous mucosa, and
Fig. 2 Enteroscopic findings. Linear ulcer (a) and irregularly shaped shallow ulcers (b) are shown under retrograde BAE. c Contact bleeding
from ulcer bed can be seen. d Intervening intestinal mucosa is apparently normal under enteroscopy
Clin J Gastroenterol (2015) 8:57–62 59
123
only ‘‘nonspecific’’ chronic inflammatory cell infiltrates are
found. In the healing process of the ulcer, submucosal fi-
brosis is restricted to the area of the mucosal defect with
minimal epithelial repair and restitution, which has been
referred to as the ‘‘ulcerative nonproliferative process’’ by
Okabe and Sakimura [7, 10].
Clinical course and therapies
The clinical course of CNSU is characterized by the re-
currence of small intestinal ulcers and stenosis even after
surgery, because efficacious medical treatment strategy has
not yet been established. Empirically, enteral nutrition
coupled with iron supplementation can temporarily im-
prove anemia and hypoproteinemia. Parenteral nutrition
can also achieve mucosal healing. However, small intesti-
nal ulcers and subsequent anemia and hypoproteinemia
recur soon after the bowel rest is stopped. Previously, pa-
tients were obliged to undergo surgery when small in-
testinal stenoses occured, but balloon dilation under
enteroscopy is now an alternative treatment for such
complications. None of the medications used for inflam-
matory bowel diseases, including 5-aminosalicylic acid,
prednisolone, and thiopurines, are effective for patients
with CNSU [6, 7, 10, 11, 13]. In our experience, we have
found no therapeutic effect of either thiopurines or anti
tumor necrosis factor-a antibody. In addition, one patient
received treatment with misoprostol which resulted in a
failure of clinical improvement. Based on the above
clinicopathologic features, a modified list of the diagnostic
criteria of CNSU was proposed in 2004 (Table 2) [6, 14].
It has been recently revealed that certain extraintestinal
manifestations can occur in CNSU (data submitted for
publication); however, patients with CNSU are free from
any complications, such as oral, skin, joint, genital, or
perianal lesions, as are found in Crohn’s disease and
Behcet disease.
Differential diagnosis
Clinical conditions that can cause small intestinal ulcers
with occasional strictures need be excluded.
Initially, Crohn’s disease should be rigorously excluded,
because both diseases share some common clinical char-
acteristics: (1) susceptible during adolescence, (2) charac-
terized by persistent anemia and hypoproteinemia, and (3)
stricturing behavior of the small intestinal lesions [15, 16].
In addition, there have been reports showing gastroduo-
denal and colonic involvement of CNSU [11, 12].
Fig. 3 Enteroscopic findings. a Concentric stenosis accompanied by shallow ulcers is found under intraoperative enteroscopy. b Spiral intestinal
stricture is found under retrograde BAE
Table 2 Diagnostic criteria of CNSU
1. Persistent and occult blood loss from the GI tract except during
bowel rest or postoperative period
2. Confirmation of characteristic small intestinal lesions by
macroscopy, radiography, or enteroscopy
(a) Circular or oblique in alignment
(b) Sharply demarcated from surrounding normal mucosa
(c) Geographic or linear in shape
(d) Multiplicity in number with\4-cm distance from each other
(e) Ulcers not reaching proper muscular layer
(f) Scarred ulcers presumed to the healing stage of those
characterized by (a)–(e)a in cases treated by bowel rest
a Depicted as symmetric and eccentric rigidity under small-bowel
radiography, and concentric or nonconcentric stricture under
enteroscopy
60 Clin J Gastroenterol (2015) 8:57–62
123
However, unlike Crohn’s disease, the intestinal lesions of
CNSU lack transmural inflammation, fissuring, fistula, and
granuloma. Furthermore, the morphologic features of the
small intestinal ulcers are completely different between the
two diseases [15, 16]. In conjunction with these histologic
and morphologic differences, neither glucocorticoid nor
thiopurines show any therapeutic effect in patients with
CNSU [6, 7, 10, 11, 13].
NSAIDs enteropathy is the second most important dif-
ferential diagnosis of CNSU. This is because circumfer-
ential thin ulcers and concentric stenosis can occur in
patients with long-term NSAID use [17, 18], and because
the ileum is the predominantly involved site [19]. How-
ever, circumferential thin ulcers in NSAIDs enteropathy
tend to occur on top of Kerckring folds and they are rarely
aligned obliquely. Furthermore, the strictures can show
spiral patterns because of the oblique nature of pre-existing
ulcers in CNSU. Finally, NSAIDs enteropathy dramatically
improves after the cessation of the causative drugs [4].
Intestinal tuberculosis is thought to be another differ-
ential diagnosis because mycobacterial species can cause
chronic inflammation in the gastrointestinal tract develop-
ing multiple circumferential ulcers. However, the small
intestinal ulcers in tuberculosis are characterized by an
irregular margin and dense mucous exudates [7]. In addi-
tion, such ulcers are usually accompanied by multiple
scarred ulcers and villous atrophy in the surrounding mu-
cosa [7]. Finally, the ileocecal region is uniformly affected
in patients with intestinal tuberculosis, and such patients
will have a positive intradermal tuberculin test or interferon
c releasing assay.
However, CMUSE, which has been mainly reported
from European countries [8, 20–22], is another differential
diagnosis. According to reports by Perlemuter et al. [8, 22],
the clinicopathologic features of CMUSE are quite similar
to those of CNSU. However, CMUSE has been suggested
to be associated with vasculitis relating to heterozygous
type I C2 deficiency [22]. In addition, CMUSE manifests
extraintestinal manifestations (peripheral neuropathy, buc-
cal aphthae, sicca syndrome, polyarthralgia, Raynaud’s
phenomenon, etc.), which are rarely seen in patients with
CNSU [6, 7, 10, 11]. Finally, steroid therapy has a
beneficial effect in CMUSE [8, 9]. Considering these dif-
ferences in clinical condition, CMUSE should be assumed
to be different from CNSU.
Genetic contribution
We have recently reviewed family histories of 13 patients
with CNSU, and found 6 patients who were offspring of
consanguineous marriage of 3� or 5�. In addition, 3 of 13
patients had siblings showing enteropathy, and 2 of them
were siblings of consanguineous marriage [23]. Based on
the segregation in offspring from consanguinity, we
speculated that CNSU is an autosomal recessive disorder
[23]. In the present case series of CNSU, 8 of 16 patients
were offspring of consanguinity marriages. In addition, 4 of
the other 8 patients who denied consanguinity in their
family pedigrees had siblings with CNSU. Such dense in-
heritance again confirms that CNSU is distinctive of her-
editary disease.
Although CNSU is obviously different from NSAID
enteropathy, both conditions share some similar morpho-
logic features, where analogous etiology of the diseases can
be postulated. In this context, Adler et al. [24] previously
reported an unusual form of enteropathy with a life-long
history of occult gastrointestinal blood loss causing iron
deficiency anemia and relapsing abdominal pain. In mid-
dle-age, the patient manifested multiple, sharply demar-
cated ulcers and stenosis in the jejunum and the ileum, and
histological examination of the resected specimens showed
only nonspecific ulcers with minimal inflammatory infil-
trates. In addition, the patient was confirmed to have in-
herited compound heterozygosity of the cytoplasmic
phospholipase A2-a (cPLA2a) gene, resulting in reduced
eicosanoid biosynthesis in platelets and leukocytes. More
recently, Brooke et al. [25] also demonstrated a homozy-
gous deletion in PLA2G4A encoding cPLA2a in patients
with CMUSE by using genome-wide single nucleotide
polymorphism homozygosity mapping combined with
whole-exome sequencing. Since cPLA2a catalyzes the
release of arachidonic acid from membrane phospholipids,
obviously impaired production of eicosanoids such as
PGE2 and thromboxane A2 in CMUSE patients can cause
multiple ulcers of the small intestine and platelet dys-
function [24, 25].
By using whole-exome sequencing, we have recently
identified the gene responsible for the development of
CNSU (data submitted for publication). Since the gene
encodes a certain kind of protein that mediates intracellular
prostaglandin levels in numerous tissues, aberrant function
of the protein causes dysregulated prostaglandin levels in
the intestinal mucosa, resulting in the development of
multiple small bowel ulcers. Although the dysregulation of
prostaglandins contributes to the pathogenesis of both
CNSU and CMUSE, genetic analyses have revealed that
the diseases are distinct clinical conditions.
Conclusions
In this review, we have described the clinicopathologic
features, differential diagnosis, and the likelihood of a
genetic contribution to CNSU. Our recent genetic analysis
greatly contributes to the diagnosis of CNSU as well as
Clin J Gastroenterol (2015) 8:57–62 61
123
differentiation from other clinical conditions showing
multiple small bowel ulcers. However, since CNSU is a
rare clinical condition, the accumulation of more patients is
mandatory to further elucidate clinical, genetic, and
pathophysiological characteristics of the disease. Eventu-
ally, effective medical therapy targeting the pathogenesis
of the disease needs to be established in order to provide a
better clinical outcome for patients with CNSU.
Acknowledgments This work was supported in part by Health and
Labour Sciences Grants for research on intractable diseases from The
Ministry of Health, Labour and Welfare of Japan.
Disclosures
Conflict of Interest: Motohiro Esaki, Junji Umeno, Takanari Kita-
zono and Takayuki Matsumoto declare that they have no conflict of
interest.
Human/Animal Rights: All procedures followed were in accordance
with the ethical standards of the responsible committee on human
experimentation (institutional and national) and with the Helsinki
Declaration of 1975, as revised in 2008(5).
Informed Consent: Informed consent was obtained from all patients
for being included in the study.
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